PROJECT SUMMARY Allogeneic hematopoietic cell transplantation is an effective therapy for patients with high risk hematologic malignancies. This is due to a well recognized graft versus tumor reaction mediated in part by donor natural killer (NK) cells. NK cell cytotoxicity against malignant cells is controlled by an array of cell surface proteins, including the killer Ig-like receptors (KIR), which interact with class 1 human leukocyte antigens (HLA) on target cells to calibrate NK cell effector function. KIR are genetically diverse: Significant inter-individual variation exists in terms of the number of KIR genes expressed and allelic polymorphism within individual KIR genes. This genetic variation determines KIR proteins with variegated capacity to activate or inhibit the NK cell when taken into consideration with the transplant recipient?s HLA. Therefore, genotyping of donor KIR/recipient HLA is a potential mechanism to define and select allogeneic donors that have more alloreactive NK cells, thereby preventing relapse in the transplant recipient. Allogeneic hematopoietic cell transplantation (allo HCT) was historically offered only to patients with high risk malignancies who had HLA matched sibling or unrelated donors. HLA-haploidentical donors are partially matched, familial donors that are available in >95% of patients, but were previously avoided as donors due to their resulting in a high incidence of graft versus host disease (GVHD) after transplantation. Recent advances in GVHD prevention using post-transplant cyclophosphamide have decreased the incidence of transplant related mortality to <10-20% after haploidentical donor allografts. Despite this, relapse occurs in 30-60% of haplotransplant recipients and is the most frequent cause of death in these patients. As haploidentical donors represent a broadly available and cost effective donor source, optimizing their efficacy is an important step in improving transplant outcomes. These results are particularly applicable to persons of ethnic and/or racial minorities, who are more frequently without a HLA matched donor option. The purpose of the proposed grant is to use KIR gene and allele typing to identify haploidentical donors with greater predicted NK alloreactivity against recipient malignant cells. Using a set of 450 donor/recipient pairs, this proposal will test the hypothesis that greater donor NK alloreactivity will result in decreased relapse and improved relapse-free survival in haplotransplant recipients. In a second aim, this proposal will address the hypothesis that HLA may be passed from recipient stromal cells to donor NK cells and will examine the resulting effects of HLA exchange on donor NK cell activation state after transplantation.